1. Field of the Invention
The present invention relates to a process for the preparation of an aminothiadiazolylacetyl halide derivative which is useful as an acylating agent for the preparation of a 7.beta.-acylaminocephalosporin derivative having excellent antimicrobial activities.
2. Description of the Related Art
To improve the antimicrobial activities of cephem compounds, various studies have heretofore been made. It has been found that, among them, chemical modification of the amino group at the 7-position of the cephalosporin skeleton is particularly useful and the formation of a 7-amido linkage with 2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid leads to a broader antimicrobial spectrum and enhanced antimicrobial activities.
For this purpose, a desired antibiotic having excellent antimicrobial activities can be prepared generally by modifying the carboxyl group of 2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid to obtain a reactive derivative and then subjecting the derivative to condensation with a corresponding 7-aminocephalosporin derivative. Examples of the reactive derivative at the carboxyl group include acid halides such the acid chloride and acid bromide, the acid anhydride, mixed acid anhydrides, active esters and active acid amides.
Although a number of reactive derivatives at the carboxyl group can be given as referred to above, acid halides such as the acid chloride and acid bromide are employed predominantly from the viewpoints of reactivity, operation efficiency and the like.
2-(5-Amino-1,2,4-thiadiazol-3-yl)acetic acid has in its molecule two active functional groups, that is, an amino group and a carboxyl group. Upon halogenation of the carboxyl group, in general, the other functional group, i.e., the amino group is first blocked with a protecting group such as a t-butoxycarbonyl group (hereinafter referred to as "Boc") and the carboxyl group is then subjected to halogenation.
For instance, Csendes et al. disclosed in Journal of Antibiotics, 36, 1020-1033(1983) a process for the synthesis of a desired antibiotic. According to the process, a mixture of oxalyl chloride and N,N-dimethylformamide (the so-called Vilsmeier reagent) is added dropwise at -10.degree. C. to a solution of 2-(5-Boc-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-oxyiminoacetic acid in ethyl acetate to convert the acid into acid chloride. Without isolation of the acid chloride a corresponding 7.beta.-aminocephalosporin derivative is added further so that to the acid chloride and the derivative are caused to condense together to yield the desired antibiotic.
In addition, Kamiya, et al. disclose in Japanese Patent Laid-Open No. 156984/1989 another process for the synthesis of a desired antibiotic. According to this process, a liquid mixture of N,N-dimethylformamide and tetrahydrofuran is cooled to -10.degree. C., followed by the addition of phosphorus oxychloride. After stirring the resulting mixture under ice cooling, 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetic acid is added at -10.degree. C. to convert it into its acid chloride as in the above-described process. Further, and then, similarly to the process described above, the resulting acid chloride is caused to condense with a corresponding 7.beta.-aminocephalosporin derivative.
Because these processes do not contain any isolation step for the acid chloride, the yield or the like of the aminothiadiazolylacetic acid derivative is not known.
Besides, Sakane et al. disclose in Japanese Patent Laid-Open No. 24389/1982 a further process. According to this process, 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetic acid with the amino group being unproteced is chlorinated with phosphorus pentachloride at -20.degree. C. in methylene chloride. Then, the resulting acid chloride is added to diisopropyl ether to precipitate 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetyl chloride.hydrochloride in a yield of 89.1%.
An acid halide is, in general, not stable, so that as the above-described Csendes et al. process or that disclosed in Japanese Patent Laid-Open No. 156984/1989, the acid halide tends to be employed for the reaction in the subsequent step without isolation and purification after the formation. The most serious drawback of these processes, however, is that, as the reaction proceeds to the subsequent reaction with the co-existence of reactive by-products formed as a result of the halogenation, these by-products undergo side reactions, leading to additional formation of many by-products. The target acid halide should, therefore, be isolated and purified from the resulting crude products containing many by-products which are relatively similar in structure and physical properties. As a result, the yield of the target acid halide drops substantially and, in some instances, the acid halide cannot have sufficient purity because some of the byproducts cannot be removed no matter what method is employed.
As the process disclosed in Japanese Patent Laid-Open No. 24389/1982, it has been attempted to remove reactive by-products, which resulted from halogenation, as much as possible by once isolating the acid halide. According to the processes which have heretofore been disclosed, the yield of the desired acid halide is low. In addition, the purity of the acid halide is insufficient, because a phosphorus-amide derivative represented by the structural formula (III) described below is by-produced unless the amino group is protected. ##STR3##
In addition, the Csendes et al. or Kamiya et al. process, which involves the protection of the amino group, requires an additional step to remove the protecting group, leading to the drawbacks that the yield is reduced due to the need for the additional step and isomerization at the iminoether bond occurs by the use of the acid. Thus, these processes are not satisfactory from the industrial viewpoint.
Even in the processes in which a reactive derivative at the carboxyl group is used instead of an acid halide, problems in reactivity, operation efficiency, safety, cost and the like have remained unsolved. Reactive intermediates produced by the prior art are also dissatisfactory from the viewpoints of purity, stability and the like.